Saxagliptin, (1S,3S,5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile of Formula I or its hydrochloride salt of Formula-II is an orally active reversible dipeptidyl peptidase-4 (DPP-4) inhibitor, which is a therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related diseases and is disclosed in U.S. Pat. No. 6,395,767 example 60.

Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb.
Saxagliptin, its hydrochloride and trifluoro acetate salts are disclosed in U.S. Pat. No. 6,395,767B2. U.S. Pat. No. 7,420,079B2 and its continuation US Pat. No. 2010/0274025 A1 disclosed process for preparing Saxagliptin and its hydrochloride, trifluoro acetate and benzoate salts, as well as Saxagliptin monohydrate. U.S. Pat. No. 7,705,033 B2 disclosed process for preparing Saxagliptin monohydrate. U.S. Pat. No. 7,214,702 B2 also disclosed similar processes for the preparation of Saxagliptin and its hydrochloride salt.
The essential steps of the processes disclosed in all the above said patents are summarized as Scheme-I below.

Tertiary butyloxy carbonyl (BOC) protected Saxagliptin of formula-VI was deprotected with aqueous hydrochloric acid, converted into Saxagliptin hydrochloride salt of formula-II, which was further treated with an alkali solution and extracted with an organic solvent to obtain the free base (1S,3S,5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile of formula-I.
The above process suffers from the drawback that the tertiary-butyloxy carbonyl (BOC) protecting group was sensitive towards acidic experimental conditions during the condensation of compounds of formula-III and IV and transformation of the amide group to cyano group subsequently. Without this protection, the amino group is available for interaction with the cyano group leading to undesirable products as explained later.
U.S. Pat. No. 7,186,846B2 disclosed a process for the preparation of Saxagliptin base through the reductive cleavage of a protected Saxagliptin (protected with trifluoro acetyl group) as shown in Scheme-II below.

Hiroshi Fukushima et al (Chem. Pharm. Bull., 56(8), 1110-1117, 2008) reported the instability of 2-cyano fluoro pyrrolidine derivatives at pH 6-8 due to intramolecular attachment of basic nitrogen to the cyano group which leads to the formation of cyclic amidine, with subsequent further transformation into diketopiperazine derivatives. Saxagliptin can also be viewed as a derivative of 2-cyano pyrrolidine which may undergo formation of the cyclic amidine through intramolecular cyclisation.
The acid salts of Saxagliptin are generally stable in solution. However, isolation of the free base (1S,3S,5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile of formula-I from its hydrochloride salt of formula-II is difficult. Scott Jones et al (OPRD 13, 1169-1176, 2009) have shown (Scheme-III below) that Saxagliptin base underwent intramolecular cyclisation to form cyclic amidine of formula-X under alkaline conditions.

Further Scott Jones et al (JOC, 76, 10332-10337, 2011) reported that, “during the development of Saxagliptin manufacturing process, it was observed that the rate of cyclisation increases monotonically with pH”. Since the resultant cyclic amidine [CA] of formula-VIII is not therapeutically active; its formation is not desirable.
All the methods disclosed in the literature and patents employ treatment of Saxagliptin hydrochloride with an alkali solution to prepare Saxagliptin base, which process is not preferable because it leads to the formation of the cyclic amidine impurity under the basic pH conditions.
Therefore there is a need for an improved, industrially applicable process to overcome the above problems.
The present invention provides new methods and compounds for use in the process for making of Saxagliptin free base of formula-I.